Gene interactions and pathways from curated databases and text-mining
Nat Cell Biol 2012, PMID: 22388891

Fbxw7α- and GSK3-mediated degradation of p100 is a pro-survival mechanism in multiple myeloma.

Busino, Luca; Millman, Scott E; Scotto, Luigi; Kyratsous, Christos A; Basrur, Venkatesha; O'Connor, Owen; Hoffmann, Alexander; Elenitoba-Johnson, Kojo S; Pagano, Michele

Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α, which recognizes a conserved motif phosphorylated by GSK3. Efficient activation of non-canonical NF-κB signalling is dependent on the elimination of nuclear p100 through either degradation by Fbxw7α or exclusion by a newly identified nuclear export signal in the carboxy terminus of p100. Expression of a stable p100 mutant, expression of a constitutively nuclear p100 mutant, Fbxw7α silencing or inhibition of GSK3 in multiple myeloma cells with constitutive non-canonical NF-κB activity results in apoptosis both in cell systems and xenotransplant models. Thus, in multiple myeloma, Fbxw7α and GSK3 function as pro-survival factors through the control of p100 degradation.

Diseases/Pathways annotated by Medline MESH: Multiple Myeloma
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Text Mining Data

Dashed line = No text mining data

Manually curated Databases

  • IRef Biogrid Interaction: RELB — NFKB2 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: NFKBIA — BTRC (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: FBXW4 — SKP1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: BTRC — BCL2L11 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: NFKB2 — NFKB2 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: BTRC — SKP1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: FBXW7 — NOTCH1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CUL1 — FBXW7 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CUL1 — FBXW7 (association, biochemical)
  • IRef Biogrid Interaction: SKP1 — FBXW7 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: SKP1 — FBXW7 (association, biochemical)
  • IRef Biogrid Interaction: NFKB2 — FBXW7 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CCNE1 — FBXW7 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: FBXW5 — SKP1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: BTRC — NFKB1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: BTRC — NFKB2 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: RBX1 — FBXW7 (association, biochemical)
  • IRef Biogrid Interaction: FBXW8 — SKP1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: FBXW2 — SKP1 (physical association, affinity chromatography technology)
In total, 17 gene pairs are associated to this article in curated databases